ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.782T>G (p.Leu261Arg) (rs765642157)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000805075 SCV001335320 uncertain significance Rasopathy 2020-03-16 reviewed by expert panel curation The c.782T>G (p.Leu261Arg) variant in PTPN11 was absent from large population studies (PM2; It was observed in several individuals whose features appear suggestive of a RASopathy; however, none were sufficiently phenotyped or received clinical diagnoses of a RASopathy (PS4 not met). This variant occurs in a region defined by the ClinGen RASopathy Expert Panel as a mutational hotspot of PTPN11 (PM1; PMID: 29493581). Additionally, the Expert Panel has defined PTPN11 as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, the clinical significance of this variant is uncertain based on RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM1, PM2, PP2.
GeneDx RCV000354323 SCV000330893 likely pathogenic not provided 2017-04-20 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the PTPN11 gene. The L261R variant has been previously identified in a child with Noonan syndrome; however, limited evidence is available for review (Grob et al., 2011). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L261R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a conserved position within the tyrosine phosphatase domain. However, in silico analysis is inconsistent in its predictions as to whether or not the L261R variant is damaging to the protein structure/function. Missense variants at the same residue (L261F/H) and in nearby residues (Q256K/R, E258D, C259S, L262R, R265Q) have been reported in the Human Gene Mutation Database in association with PTPN11-related disorders (Stenson et al., 2014). Therefore, this variant is likely pathogenic.
Invitae RCV000805075 SCV000945018 uncertain significance Rasopathy 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 261 of the PTPN11 protein (p.Leu261Arg). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PTPN11-related conditions. ClinVar contains an entry for this variant (Variation ID: 280939). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Leu261 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been observed in individuals with PTPN11-related conditions (PMID: 28074573, 22253195, 23756559, 22465605) suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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